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CP > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What is drug disposition?

A

Drug disposition refers to all the processes involved in the absorption, distribution, metabolism and excretion of drugs in a living organism. These processes influences the free drug concentration that is achieved in the plasma after a drug has been administered.

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2
Q

Does drug dose or free drug concentration has a stronger relationship with pharmacological effect?

A

Free drug concentration

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3
Q

What is pharmacokinetics?

A

Pharmacokinetics is the study of concentration-time profile of a drug in the body.

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4
Q

What are the three important pharmacokinetics parameters?

A

Clearance, volume of distribution, half-life

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5
Q

What is therapeutic window and how is it determined?

A

Therapeutic window refers to the range of drug concentrations where the drug is effective and cause minimal toxicity. It is determined by matching the drug concentrations to therapeutic and adverse effects. (allows more rational dosing)

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6
Q

Why is pharmacokinetics important? (2 reasons)

A

1) allow us to identify the therapeutic window for rational dosing
2) allow us to identify the optimal route of administration(poorly absorbed by gut?) and schedules (if it is rapidly eliminated?) of dosing e.g. oral or IV, once or 3x daily

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7
Q

What is clearance?

A

Clearance(L/hr) describe the relationship between the concentration(mg/L) of the drug in the plasma and the elimination rate(mg/h) of the drug. It is a constant for a particular drug in a particular patient, therefore elimination rate is proportional to drug concentration.

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8
Q

What is drug elimination and what are the 3 main processes involved?

A

Drug elimination is the processes by which a drug is removed from the body.

  • metabolism (predominantly in liver)
  • biliary excretion in liver
  • excretion by glomerular filtration or tubular secretion in the kidney.
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9
Q

How does the hepatic clearance of a drug affect the route of administration?

A

A drug with high hepatic clearance will not be suitable for oral dosing because it will get eliminated during the first pass metabolism. Low hepatic clearance on the other hand will be suitable.

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10
Q

Give an example of a drug that is cleared by multiple routes (kidey and liver)

A

digoxin

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11
Q

What is maintenance dose rate?

A

It is the dose rate required to achieve and maintain a target concentration. Usually we want to achieve our target concentration at a steady rate within the therapeutic window of the drug.

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12
Q

What does steady state means in terms of drug concentration? And how are they achieved with oral and IV dosing?

A

Steady state occurs when the rate of drug administration = rate of drug elimination. For IV dosing, an IV infusion can be administered to keep drug concentration at steady state. For oral dosing, it is reached when the peak and trough concentration achieved after each dose is similar.

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13
Q

What are the three types of clearance and in what order reaction do they occur (describe the relationship between the conc and the elimination and time?

A
  • Constant CL(first order/linear elimination)- as conc increases, more enz recruited to metabolise drug, increased elimination rate. e.g. GFR. CL does not change and is independent of concentration and organ blood flow.
  • Conc dep CL (mixed order/non-linear elimination)- elimination mechanisms become saturated in which case clearance is concentration dep.
  • Flow dep CL: CL approximates organ blood flow, for drugs that are rapidly cleared and clearance is limited by the delivery of drug to eliminating organ
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14
Q

What is drug distribution and what parameter defines it?

A

Drug distribution is the reversible movement of drug between body compartments once it has entered the systemic circulation. (transfer of drug from systemic circulation to various body compartments). Defined by parameter- volume of distribution (V)

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15
Q

What is volume of distribution?

A

The volume of distribution describes the relationship between amount of drug in the body and the plasma drug concentration. It is an apparent volume. V= amount/conc. The apparent volume of distribution is the volume that the drug must be dissolved in to give a concentration equivalent to that found in plasma.

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16
Q

What are some factors that determine the volume of distribution?

A
  • body mass and composition
  • tissue blood flow
  • tissue binding (increases V)
  • plasma protein binding (decreases V)
  • physico-chemical properties of the drug (size, ionisation etc)
  • natural barriers
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17
Q

How is V (Volume of distribution) useful in pharmacology?

A

The main use of V is to calculate the loading dose to ensure that target concentrations are reached quickly. The volume that the drug needs to distribute affects the time taken to reach steady state and also time for elimination but NOT steady state concentration.

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18
Q

What is drug absorption?

A

The transfer of drug from administration site to the systemic circulation. For IV injection- instantly 100% absorped. For oral dose, the drug needs to pass through biological membranes- absorbed through gut wall, then enters liver via portal vein and avoid first pass metabolism before they reach systemic circulation.

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19
Q

Compare the drug plasma concentration and time relationship for oral and IV dose.

A

For IV- administered directly into systemic circulation –> drug absorbed completely and immediately –> peak conc at t=0 and declines with first order reaction pattern.
For oral- not all of the drug is absorbed into the systemic circuit and it takes time to be absorbed –> area under curve usually less than IV, peak concentration less that IV (peak achieved when elim rate = abs rate, decline pattern slightly different than IV because drug is still being absorbed even though clearance is the same.

20
Q

What are the two factors of drug absorption that are important for us to know?

A
  • rate of absorption (how quickly does the drug transfer from administration site to systemic circulation- faster rate, faster onset
  • extent of absorption (- described via bioavailability- how much of the administered drug enters the systemic circulation)
21
Q

What are the two parts to consider in oral drug absorption? Write the equation that determines bioavailability (overall extent of drug absorption).

A
  • The extent of oral drug absorbed into the portal vein from gut (f)
  • Hepatic extraction ratio (ER): the fraction of drug entering the liver that is eliminated/extracted

F = f(1-ER)

22
Q

What determines the f?

A
  • properties of drugs: small, non-ionised, lipophilic (diffuse through easily)
  • metabolism (enzymes in gut wall that can break down drugs)
  • efflux (drug transporters in the gut wall that will efflux drug back into the gut lumen)
23
Q

What determines ER?

A
  • blood flow (slower, more time for liver to clear, greater ER)
  • ability of liver to clear the drug (intrinsic clearance of the liver)
24
Q

What is drug metabolism?

A

Drug metabolism the the biotransformation of drug which involves enzyme catalysed process that make chemical changes to the drugs: building it up/breaking down into metabolites.
Typically generate more polar metabolite to allow excretion via urine or bile and decrease bioactivity (harder to diffuse across cell membrane). usually drugs are lipophilic

25
Q

Why is drug metabolism important? (6 points)

A
  • it influences the concentration time profile of drug (fast metabolism, low bioavailability, low conc)
  • it is a major route of drug elimination (generally inactivates drug)
  • can increase drug activity (activation of prodrug e.g. codeine –> morphine)
  • production of toxic metabolites (e.g paracetamol)
  • can explain drug-drug interactions
  • source of interpatient variability
26
Q

What are the possible sites of metabolism?

A
  • liver (major site- all oral drugs have to avoid first pass metabolism)
  • intestinal wall (CYP450 enzymes)
  • GI tract (gut bacteria and proteases)
  • plasma (esterases- prodrug activation)
  • lungs (metabolism of aerosol sprays)
27
Q

What are the types of metabolic reactions?

A
  • oxidation (addition of oxygen with removal of electron H+)
  • reduction (add H+ with/without loss of oxygen atom
  • hydrolysis (addition of water which usually resulted in bond cleavage.
  • conjugation (addition of endogenous substrate to increase molecular mass, polarity, water solubility
28
Q

What are the cytochrome P450 enzymes?

A

They are a superfamily of metabolising (oxidative) enzymes- most common drug metabolising enzymes and most common reaction is a monooxygenase reaction. the proteins sit within liver cells.

29
Q

What are the factors that affect CYP function?

A
  • gene expression/ gene polymorphism

- inhibitor/inducers

30
Q

What are the clinically relevant substrates and drug interactions for CYP1A2?

A
  • catalyse oxidation of theophylline into caffeine
    inhibition: cimetidine
    induction: tobacco, bbq meat, cruciferous veges
    (smoking –> more theophylline dose required)
31
Q

What are the clinically relevant substrates and drug interactions for CYP2E1?

A
  • catalyse oxidation of paracetamol
    induction: ethanol- chronic ethanol consumption increases CYP2E1 expression promoting paracetamol metabolism to its toxic metabolite (needs high doses of paracetamol for it to be problematic.
32
Q

What are the clinically relevant substrates and drug interactions for CYP2D6?

A
  • catalyse oxidation of debrisoquine, tricyclic antidepressants (amitriptyline), codeine–> morphine
    inhibition: fluoxetine
    genetic polymorphisms - big range of phenotype –> drug companies try to avoid compounds that are substrates for CYP2D6
33
Q

What are the clinically relevant substrates and drug interactions for CYP2C9?

A
  • catalyse oxidation of S-warfarin
    Inhibition: cimetidine
    genetic polymorphism exists
34
Q

What are the clinically relevant substrates and drug interactions for CYP2C19?

A
  • catalyse oxidation of clopidogrel
    inhibition: omeprazole
    genetic polymorphism exists
35
Q

What are the clinically relevant substrates and drug interactions for CYP3A4?

A

most common drug metabolising enzyme. found in liver, intestines also kidney, lung, placenta and uterus

  • catalyse oxidation of simvastatin and felodipine
    inhibition: erythromycin, grapefruit juice
    induction: rifampicin, St John’s wort
36
Q

What do inherited differences in drug metabolising enzymes influence?

A
  • plasma pharmacokinetics (clearance)
  • drug safety (adverse effects)
  • drug effectiveness
37
Q

What are the four drug metaboliser traits (phenotypes)?

A
  • PM: poor metaboliser
  • IM: intermediate metaboliser
  • EM: extensive metaboliser
  • UM: ultra-rapid metaboliser
38
Q

What is genetic polymorphism?

A

When two or more clearly different phenotypes exist in the same population is called polymorphism. Genetic polymorphism is when gene mutations result in altered protein and altered phenotype. When the distinct form of the gene occurs in at least 1% of the population it is a genetic polymorphism.

39
Q

What is genetics of PM and what are the potential consequences?

A

PM are those who inherited loss of function of a drug metabolising enzyme and can result in no enzyme activity. (normally autosomal recessive Mendelian manner- homozygous for null function variant). It may lead to higher drug levels in the blood which might result in increased risk of an adverse drug reaction compared with individuals with ‘normal’ metabolism.

40
Q

What sort of metabolic ratio (drug/metabolite plasma conc) do we see in PM and EM?

A

PM- high ratio

EM- low ratio

41
Q

How does the genotype of patients help us with drug dosage?

A

If its AA- EM: normal
If its Aa (codominant)- IM: normally half the clearance: less
If its aa - PM: alternative etc
So we can know the extent of functional change in the variant allele and we can often accurately determine the amount of change you will see.

42
Q

Why do we need to consider the wideness of therapeutic index? Use omeprazole as an example.

A

Omeprazole is metabolised by CYP2C19. For people who are PM for this, they will have elevated omeprazole levels when administered a normal dose. If the therapeutic index is wide (wide range of omeprazole conc effectively suppress gastric acid secretion), then that matters less compared to if its narrow that it can easily produce toxic effect.

43
Q

How does clopidogrel work for PM/UM and how does that affect dosage?

A

Clopidogrel is a pro drug and requires the CYP2C19 to activate it. PM will mean that there will be low formation of active metabolite, while UM will result in higher than normal activity.
UM- lower dose
PM- alternative drug

44
Q

What are the difference in outcome between conventional therapy and genotype guided therapy?

A

better patient outcome for genotype guided therapy

45
Q

Describe how irinotecan works and the associated metabolising enzyme(its variant and effects)..

A

Irinotecan (SN-38) is a drug used to treat colorectal cancer. It has a very narrow therapeutic index (because it works but inhibiting DNA of any replicating cells..). - can lead to severe-life threatening neutropenia and GI damage. It is eliminated via hepatic glucuronidation catalysed by UGT1A1 enz. There is a variant of this enz that reduces transcription by 75% (25% less enz), so homozygous for this variant–> 50% lower enzyme activity. –> increased risk for neutropenia.

46
Q

Describe how Azathioprine works and the associated metabolising enz (its variant and effects)..

A

Azathioprine is an immunosuppressive drug which is a guanine analog that acts as an ‘antimetabolite’. It interferes with how well leucocytes process guanine and how they use them. It is a pro drug of 6-mercaptopurine which is metabolised to inactive part by TMPT. (major route of elimination). TMPT have a few non-functional variant alleles. Homozygous variant for TMPT are at increased risk of life-threatening myelosuppression at standard dose- should receive 10 fold lower dosage.

CP (3 decks)

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